CN112724103A - Isopromazine specific impurity and analysis method and removal method thereof - Google Patents
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Abstract
The invention discloses an isobutylazine specific impurity, and an analysis method and a removal method thereof. The analysis method can effectively detect specific impurity Tt-2 by combining high performance liquid chromatography with an ultraviolet detector, and the impurity can not be detected by the prior EP and USP methods. The removal method can effectively remove specific impurity Tt-2 and can also remove the specific impurity Tt-2And other process impurities further improve the purity and the properties of the product, and have great significance for subsequent research and development of the product.
Description
Technical Field
The invention relates to but is not limited to the field of chemical medicine, in particular to a specific impurity Tt-2 of isobutylazine, namely 3- (10H- [3,10' -diphenothiazine ] -10-yl) -N, N, 2-trimethylpropan-1-amine, and an analysis method and a removal method thereof.
Background
Isobutylazine is the free base of isobutylazine tartrate (Trimeprazine tartrate). The product can be used for treating skin pruritus, neurosis, mental uneasiness, infantile dysphoria, and cough.
The structural formula, molecular formula and molecular weight of the isobutylazine are as follows:
US2837518 (1958) discloses a process for the preparation of isobutylazine: dissolving phenothiazine in xylene, heating to 130 ℃, adding sodium amide, and carrying out reflux reaction for 2 hours; dripping 1-chloro-2-methyl-3-dimethylamino propane xylene solution (0.61N), performing reflux reaction for 20 hours to obtain the reaction solution of the isobutyloxazine, and then performing quenching, washing, liquid separation and concentration to obtain a crude product of the isobutyloxazine.
Disclosure of Invention
The following is a summary of the subject matter described in detail herein. This summary is not intended to limit the scope of the present application.
In the process for preparing the isobutylazine (for example, US2837518), the specific impurity Tt-2-3- (10H- [3,10' -diphenothiazin ] -10-yl) -N, N, 2-trimethylpropan-1-amine is an impurity which is inevitably generated, but has the similar property to the isobutylazine, can form a salt with tartaric acid, and the salt-forming step is difficult to remove. But the promethazine has small polarity, is easy to dissolve in petroleum ether, and has smaller polarity of impurity Tt-2, so that the impurity removal by crystallization is difficult. The impurity was not reported in USP and EP, and Tt-2 was not detected by the analytical methods provided.
The invention provides a specific impurity Tt-2 of isobutylazine, the chemical structure of the specific impurity is as follows:
on the other hand, the invention provides an analysis method of the specific impurity Tt-2, or the specific impurity Tt-2 and the isobutyloxazine tartrate, wherein the analysis method comprises the steps of combining a high performance liquid chromatography with an ultraviolet detector, adopting a chromatographic column which takes octadecyl bonded silica gel as a filling agent, taking an ammonium acetate aqueous solution/acetonitrile/methanol system as a mobile phase, and carrying out gradient elution, wherein the flow rate is 1.3ml/min, and the ultraviolet detection wavelength is 253 nm.
In the analytical method of the present invention, the size of the column may be 5 μm, 4.6mm × 150 mm.
In the analytical method of the present invention, the concentration of the aqueous ammonium acetate solution was 3.854 g/L.
In the analysis method, the mobile phase consists of a mobile phase A and a mobile phase B, wherein the mobile phase B is a mixture of acetonitrile and methanol in a volume ratio of 20: 80; mobile phase a is a mixture of a 50:50 volume ratio of aqueous ammonium acetate solution to the mobile phase B.
In the analytical method of the present invention, the procedure of the gradient elution may be:
in an analysis method of the present invention, the high performance liquid chromatography is configured to:
a chromatographic column: octadecyl bonded silica gel as filler, 5 μm, 4.6mm × 150mm chromatographic column;
column temperature: 40 ℃;
flow rate: 1.3 ml/min;
detection wavelength: 253 nm;
mobile phase A: 3.854g/L ammonium acetate (acetonitrile: methanol: 20:80 (vol.)) -50: 50 (vol.);
mobile phase B: acetonitrile to methanol 20 to 80 (volume ratio).
In the analysis method, the blank solvent in the high performance liquid chromatography does not interfere with the determination of the impurity Tt-2, and the separation degree between the isobutylazine tartrate or the isobutylazine and other component peaks is more than or equal to 1.5.
In the assay of the invention, the assay may be qualitative and/or quantitative with respect to the specific impurity and/or the isobutylazine.
In one analytical method of the present invention, the degree of separation of the isobutylazine tartrate from the impurities and the relative retention times thereof are as follows:
on the other hand, the invention provides a preparation method of the above-mentioned isobutylazine specific impurity, comprising the following steps:
1) completely dissolving the crude product of the isobutylazine in an aprotic organic solvent 1 under a heating condition;
2) reducing the temperature, standing, cooling and crystallizing;
3) pouring out the supernatant after crystallization, and washing the crystal by using an aprotic organic solvent 2; optionally, repeating steps 1) to 2) on the washed crystals;
4) collecting the supernatant and the flushing fluid obtained in the step 3), and separating by a column chromatography purification mode to obtain the specific impurity Tt-2.
In another aspect, the present invention provides a method for purifying (or removing) an isobutylazine specific impurity, Tt-2, the method comprising the steps of:
1) completely dissolving the crude product of the isobutylazine in an aprotic organic solvent 1 under a heating condition;
2) reducing the temperature and crystallizing;
3) pouring out the supernatant after crystallization, and washing the crystal by using an aprotic organic solvent 2; optionally, repeating steps 1) to 2) on the washed crystals;
4') collecting the crystals obtained in the step 3) to obtain the finished product of the final prepared promethazine.
In the above-mentioned production method or purification method (or removal method), the aprotic organic solvent 1 and the aprotic organic solvent 2 are each independently selected from one or a mixture of both of petroleum ether and ethyl acetate; optionally, when a mixture of petroleum ether and ethyl acetate is adopted, the weight ratio of the petroleum ether to the ethyl acetate can be 1 (0.2-4), 1 (0.3-2), 1 (0.4-1) or 1: 0.5.
In the preparation method or the purification method (or the removal method), the weight ratio of the crude isobutylazine in the step 1) to the aprotic organic solvent 1 is 1 (0.2-2), or 1 (0.2-1).
In the above-mentioned preparation method or purification method (or removal method), the heating in the step 1) is carried out to a temperature of 35 to 55 ℃, 35 to 50 ℃, 40 to 55 ℃, or 40 to 50 ℃.
In the above-mentioned preparation method or purification method (or removal method), the temperature is lowered to 10 ℃ to 25 ℃ in the step 2).
In the above preparation method or purification method (or removal method), the crystallization time in the step 2) is: 15 to 25 hours.
In the above-mentioned production method or purification method (or removal method), the number of times of repeating steps 1) to 2) in the step 3) is: 3-5 times.
In the preparation method, the eluent in the column chromatography purification mode in the step 4) is a single petroleum ether solvent.
On the other hand, the invention provides a refined isobutylazine product obtained by the purification method (or the removal method), wherein the residual quantity of specific impurity Tt-2 in the refined isobutylazine product is less than or equal to 0.20%.
Additional features and advantages of the application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the application. Other advantages of the present application may be realized and attained by the instrumentalities and combinations particularly pointed out in the specification and the drawings.
Drawings
The accompanying drawings are included to provide an understanding of the present disclosure and are incorporated in and constitute a part of this specification, illustrate embodiments of the disclosure and together with the examples serve to explain the principles of the disclosure and not to limit the disclosure.
FIG. 1 is a test profile of specificity of the analytical method of example 1;
FIG. 2 is a graph of the purity of the crude form of the isobutylazine of example 2;
FIG. 3 is a mass spectrum of impurity Tt-2 of example 3;
FIG. 4 is the hydrogen nuclear magnetic resonance spectrum of impurity Tt-2 of example 3;
FIG. 5 is the nuclear magnetic resonance carbon spectrum of impurity Tt-2 of example 3;
FIG. 6 is a graph of the purity of the first crystallization in example 4;
FIG. 7 is a graph of the purity of the second crystallization in example 4;
FIG. 8 is a graph showing the purity of the third crystal in example 4;
FIG. 9 is a graph of the purity of the isoethazine of the comparative example.
Detailed Description
Hereinafter, embodiments of the present invention will be described in detail in order to make the objects, technical solutions and advantages of the present invention more apparent. It should be noted that the embodiments and features of the embodiments in the present application may be arbitrarily combined with each other without conflict.
In the examples of the present invention, unless otherwise specified, the experimental procedures described are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the main raw materials, reagents and solvents used in the experiment are all chemical pure products or analytically pure products sold in the market, and are directly used without purification.
Example 1
This example is a specific test performed by using the analysis method provided in this specification, and the impurity a, the impurity B, and the impurity C of the isobutylazine tartrate are all impurities corresponding to european pharmacopoeia EP 9.0.
The instrument comprises the following steps: agilent 1260 high performance liquid chromatograph
Column: c18，5μm，4.6mm×150mm
Blank solvent: i.e. diluent (acetonitrile: water 20:80, volume ratio)
Isobutyl tartrate stock solution: accurately weighing 35mg of the isobutylazine tartrate standard substance, putting the isobutylazine tartrate standard substance into a 50ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the isobutylazine tartrate standard substance.
And (3) isobutylazine tartrate test solution: accurately transferring 5ml of the isobutylazine tartrate stock solution into a 10ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the compound.
Impurity a stock solution: weighing 1mg of impurity A, placing the impurity A in a 10ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the product.
Impurity B stock solution: weighing 1mg of impurity B, placing the impurity B in a 10ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the product.
Impurity C stock solution: weighing 1mg of impurity C, placing the impurity C in a 10ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the product.
Impurity Tt-2 stock solution: accurately weighing 25mg of impurity Tt-2, placing the impurity Tt-2 in a 100ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the product.
Impurity Tt-2 test solution: accurately transferring 1.0ml of impurity Tt-2 stock solution into a 10ml measuring flask, adding a diluent to a constant volume, and shaking up to obtain the final product.
Mixing the solution: accurately transferring 5ml of the isobutylazine tartrate stock solution, 1ml of the impurity A stock solution, 1ml of the impurity B stock solution, 1ml of the impurity C stock solution and 1ml of the impurity Tt-2 stock solution into a 10ml measuring flask, metering the volume by using a diluent, and shaking uniformly to obtain the product.
The determination method comprises the following steps:
the blank solvent was added alone, and it was confirmed that the blank solvent did not interfere with the measurement of Tt-2 as an impurity.
And respectively injecting an isobutylazine tartrate test solution, an impurity A stock solution, an impurity B stock solution, an impurity C stock solution and an impurity Tt-2 test solution, and determining the peak-off time of each component.
The mixed solution was injected, and a chromatogram was recorded to confirm the degree of separation between the peaks of each component (see FIG. 1).
The structures of impurities A, B and C are as follows (EP 9.0):
example 2
50g of phenothiazine and 650ml of xylene are added into a dry reaction bottle, and the mixture is heated and dissolved. 14.7g of sodium amide is added, and the reaction is refluxed for 2 hours. 44.4g N, xylene (500ml) solution of N-dimethylamino-3-chloro-2-methylpropane was added dropwise thereto, and the mixture was refluxed for 20 hours. Cooling, adding dilute hydrochloric acid for quenching, separating liquid, adjusting the pH of the water phase to 9-10, and extracting with ethyl acetate; the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to dryness to give 67.5g of a crude product of isobutylazine. The purity of the isobutylazine was 97.84%, and the content of impurity Tt-2 was 1.77% (see fig. 2, the correction factor for the impurity was 0.5, and the corrected impurity was 0.89%, the same applies below).
Example 3
7.0g of the crude isobutylazine (prepared in example 2) was added to a clean reaction flask, 5.6g of petroleum ether and 2.8g of ethyl acetate were added, and the mixture was heated to an internal temperature of 40 to 50 ℃ to dissolve. And after the liquid in the reaction bottle is clear and transparent, cooling to 20 ℃, stirring and crystallizing for 15 hours. Filtration, washing with 5.0g of petroleum ether and drying gave 3.22g of off-white solid powder. Further, the crystallization was repeated 1 time with 2.58g of petroleum ether and 1.29g of ethyl acetate to obtain 1.2g of an off-white solid powder having an impurity Tt-2 content of 0.24% (corrected impurity: 0.12%) and a yield of 24%.
Concentrating the mother liquor, enriching, and purifying by column chromatography (eluent: petroleum ether) to obtain 0.1g solid, namely impurity Tt-2. [ M + H ]]+496.1881 (see fig. 3, instrument: Agilent G6520Q-TOF, + ESI);1H-NMR (see FIG. 4,the instrument comprises the following steps: brucker AM-400NMR Spectrometer, CDCl3)：δH 6.23–7.22,δH 4.06(1H,dd,J＝5.3,13.4Hz),3.65(1H,dd,J＝7.9,13.4Hz),2.32(1H,m),1.09(3H,d,J＝6.1Hz),2.27(6H,s),2.43(1H,m),2.27(1H,overlap)。13C-NMR (see FIG. 5, Instrument: Brucker AM-400NMR Spectrometer, CDCl)3)：δ145.79，145.10，144.28，135.22，129.92，129.79，128.02，127.74，127.50，126.83，126.64，125.45，122.99，122.39，119.91，117.40，116.31，115.86，64.71，52.32，46.03，28.89，17.24。
Example 4
10.0g of the crude isobutylazine (prepared in example 2) was added to a clean reaction flask, 5.0g of petroleum ether was added, and the mixture was heated in a constant temperature magnetic stirrer to an internal temperature of 40 to 50 ℃. And after the liquid in the reaction bottle is clear and transparent, turning off stirring, cooling to 15-25 ℃, and standing for 18-24 hours. The resulting crystals were large, sticky-wall crystals and the supernatant was poured into a beaker. The surface of the crystals was washed with 2.0g of petroleum ether and the washing solution was also poured into a beaker. At this time, the crystal was examined, and the content of impurity Tt-2 was 1.10% (see FIG. 6, which indicates an area normalization method unless otherwise specified). The crystallization was repeated 1 time, and the impurity Tt-2 content was 0.39% (see FIG. 7). The crystallization was repeated 1 more times, and the content of the impurity Tt-2 became 0.31% (see fig. 8, corrected impurity 0.15%). 7.4g of an isobutylazine refined product is obtained, the purity is 99.39 percent, and the yield is 74 percent.
Example 5
5.0g of the crude isobutylazine (prepared in example 2) was added to a clean reaction flask, 1.5g of petroleum ether was added, and the mixture was heated in a constant temperature magnetic stirrer to an internal temperature of 40 to 50 ℃. And after the liquid in the reaction bottle is clear and transparent, turning off the stirring, cooling to room temperature, and standing for 18-24 h. The resulting crystals were large, sticky-wall crystals and the supernatant was poured into a beaker. The surface of the crystals was washed with 1.0g of petroleum ether and the washing solution was also poured into a beaker. The crystallization was repeated 3 times, and the content of impurity Tt-2 became 0.38% (corrected impurity 0.19%). The yield of the promethazine is 78 percent with purity of 99.25 percent and purity of 3.9 g.
Example 6
5.0g of the crude isobutylazine (prepared in example 2) was added to a clean reaction flask, 5.0g of petroleum ether was added, and the mixture was heated in a constant temperature magnetic stirrer to an internal temperature of 40 to 50 ℃. And after the liquid in the reaction bottle is clear and transparent, turning off the stirring, cooling to room temperature, and standing for 18-24 h. The resulting crystals were large, sticky-wall crystals and the supernatant was poured into a beaker. The surface of the crystals was washed with 1.0g of petroleum ether and the washing solution was also poured into a beaker. The crystallization was repeated 2 times, and the content of the impurity Tt-2 became 0.25% (corrected impurity 0.12%). 2.8g of an isobutylazine refined product is obtained, the purity is 99.56 percent, and the yield is 56 percent.
Comparative examples
5.0g of the crude isobutylazine (prepared in example 2) was added to a clean reaction flask, 16.0g of ethanol was added, and the mixture was dissolved by stirring at room temperature. Controlling the internal temperature to be 25-30 ℃, dripping about 20.0g of purified water until the system is slightly turbid, keeping the temperature and continuously stirring for 1-2 hours. After the solid is precipitated, 20.0g of purified water is slowly dropped for more than 2 hours. After the dripping is finished, cooling to 10-15 ℃, and stirring for 2 h. Filtering, washing a filter cake with purified water, and drying to obtain 4.8g of the isobutylazine, wherein the yield is 96%, the purity is 97.45%, and the content of an impurity Tt-2: 2.16% (corrected impurity 1.08%) (see FIG. 9). The impurity Tt-2 cannot be removed.
The present application describes embodiments, but the description is illustrative rather than limiting and it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the embodiments described herein.
Claims (11)
1. An isobutylazine specific impurity having the chemical structure shown below:
2. the method for analyzing specific impurities or the isobutylazine thereof as claimed in claim 1, comprising the step of combining high performance liquid chromatography with an ultraviolet detector, using a chromatographic column using octadecyl bonded silica gel as a filler, using an ammonium acetate aqueous solution/acetonitrile/methanol system as a mobile phase, and performing gradient elution at a flow rate of 1.3ml/min and an ultraviolet detection wavelength of 253 nm.
3. The assay of claim 2, wherein the concentration of the aqueous ammonium acetate solution is 3.854 g/L; and/or
The mobile phase consists of a mobile phase A and a mobile phase B, wherein the mobile phase B is a mixture of acetonitrile and methanol in a volume ratio of 20: 80; the mobile phase A is a mixture of ammonium acetate water solution and the mobile phase B in a volume ratio of 50: 50; gradient elution was performed.
4. The assay of claim 2 or 3, further comprising qualitatively and/or quantitatively determining the specific impurity and/or the isobutylazine.
5. The method of removing the isobutylazine-specific impurity of claim 1 comprising the steps of:
1) completely dissolving the crude product of the isobutylazine in an aprotic organic solvent 1 under a heating condition;
2) reducing the temperature and crystallizing;
3) pouring out the supernatant after crystallization, and washing the crystal by using an aprotic organic solvent 2; optionally, repeating steps 1) to 2) on the washed crystals;
4) collecting the crystals obtained in the step 3) to obtain the finally prepared promethazine fine product.
6. The removal method according to claim 5, wherein the aprotic organic solvent 1 and the aprotic organic solvent 2 are each independently selected from one or a mixture of two of petroleum ether and ethyl acetate; optionally, when the mixture of the petroleum ether and the ethyl acetate is adopted, the weight ratio of the petroleum ether to the ethyl acetate is 1 (0.2-4), 1 (0.3-2), 1 (0.4-1) or 1: 0.5.
7. The removal method of claim 5, wherein the weight ratio of the crude isobutylazine to the aprotic organic solvent 1 in the step 1) is 1 (0.2-2) or 1 (0.2-1).
8. The removal method according to claim 5, wherein the heating in step 1) is performed to a temperature of 35 ℃ to 55 ℃, 35 ℃ to 50 ℃, 40 ℃ to 55 ℃, or 40 ℃ to 50 ℃.
9. The removal method according to any one of claims 5 to 8, wherein the temperature is lowered to 10 ℃ to 25 ℃ in the step 2); and/or
The crystallization time is 15-25 hours.
10. The removal method according to any one of claims 5 to 8, wherein the number of times steps 1) to 2) are repeated in step 3) is 3 to 5 times.
11. The promethazine refined product obtained by the removal method according to any one of claims 5 to 10, wherein the residual quantity of specific impurity Tt-2 in the promethazine refined product is less than or equal to 0.2%.
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